1. 04-26-12 Part B Autoimmune Diseases

2. 04-12-12 Part B Autoimmune Diseases Effector mechanisms of autoimmune disease Endocrine glands as special targets for autoimmunity Thyroid gland (Grave’s disease, etc) Islets of Langerhans (Diabetes) Adrenal gland (Addison’s disease) Systemic autoimmune diseases - autoimmunity against common autoantigens (SLE) Rheumatoid diseases (rheumatoid arthritis) Autoimmune diseases of the nervous system (MS and myasthenia gravis) Genetic and environmental factors that predispose to autoimmune disease – breaking T cell tolerance

3. Autoimmune disease Negative selection eliminates self reactive lymphocytes Autoimmune diseases caused by body responding to self antigens; failure of self-tolerance Relatively common; 5% of population (7-8 people in class) Caused by self-reactive Abs or inflammatory T cells MHC genes involved; genetically based Common sources for autoimmune Ags: Reaction to bacterial and viral Ags similar to self Ags immune system can’t discriminate Tissue injury (eg heart attack) can release self Ags creating autoantibodies

4. The effector mechanisms of autoimmunity resemble those of certain hypersensitivity reactions (P13.2) (Type II)

6. Figure 11-2 RBC destruction in autoimmune hemolytic anemia (P13.3)

7. Figure 11-3 Autoantibodies specific for type IV collagen react with the base membrane of kidney glomeruli, causing Goodpasture's syndrome (P13.4)

8. Endocrine glands secrete tissue-specific proteins that make likely autoimmune targets. Hormone secretion into the blood makes endocrine cells highly vascularized, facilitating interactions with immune cells and molecules. Loss of endocrine function has drastic systemic effects, causing disease and death. Autoimmune diseases target a single type of epithelial cell within the endocrine gland, called “organ-specific autoimmune diseases”

9. Figure 11-4 (P13.5)

10. Figure 11-5 Grave's Disease (P13.6)

11. Chronic thyroiditis (Hashimoto disease) Thyroid loses capacity to make thyroid hormones CD4 TH1 response favors cell-mediated effectors Lymphocytes infiltrate and destroy thyroid tissues Patients become hypothyroid, can’t make thyroid hormones Ectopic lymphoid tissue can form at sites inflamed by autoimmune disease = “tertiary lymphoid” organ Lymphoid neogenesis resembles formation and function of secondary lymphoid tissue but without lymphatics or capsule

12. Hashimoto's thyroiditis (P13.7)

13. Figure 11-8 Pancreas from a patient with Type 1 insulin-dependent diabetes mellitus (destruction of islet cells  -cells) (P.13.9) Note infiltration of the islet by lymphocytes

14. Figure 11-1 part 2 of 3 The effector mechanisms of autoimmunity resemble those of certain hypersensitivity reactions (P13.2) (Type III)

15. Glomerulonephritis (22.7)

16. Immune complex deposition in the basement membrane of kidney glomeruli in systemic lupus erythematosus (P13.10) neutrophils Fluorescent anti-Ig antibodies

17. Figure 11-10 The chacracteristic facial rash of lupus erythromatosus is caused by deposition of immune complexes in the skin (P13.11)

18. Rheumatic diseases are autoimmune in nature (P13.12)

19. Figure 11-1 part 3 of 3 The effector mechanisms of autoimmunity resemble those of certain hypersensitivity reactions (P13.2) (Type IV)

20. Figure 11-12 Rheumatoid arthritis is caused by inflammation of the joints exacerbated by rheumatoid factor (anti-immunoglobulin antibodies) (P13.13)

21. Figure 11-13 Treatment of rheumatoid arthritis with anti-TNR-  (P13.14)

22. Killing of B cells by anti-CD20 antibody and NK cells (P13.15)

23. Figure 11-15 Diseases mediated by antibodies against cell-surface receptors (P13.17)

24. Figure 11-14 Myasthenia gravis is caused by autoantibodies against the acetylcholine receptor (P13.16)

25. Genetic and Environmental Factors and Autoimmune Disease All autoimmune diseases involve breaking T-cell tolerance Incomplete deletion of self-reactive T cells in the thymus causes autoimmune disease Regulatory T cells protect cells/tissues from autoimmunity HLA is the dominant genetic factor affecting susceptibility to autoimmune disease Noninfectious environmental factors (eg smoking) influence the course of autoimmune disease Loss of oral tolerance leads to inflammation, autoimmunity Infections can trigger autoimmune disease

26. Figure 11-16 Arrest and death of autoreactive B cells in secondary lymphoid tissue (P13.19)

27. Figure 11-21 CTLA-4 is involved in the action of regulatory T cells (P13.22)

28. Figure 11-28 Celiac disease is caused by inflammation of the small intestines due to CD4 T cells responding to peptides derived from wheat gluten (P12.40) Celiac disease = Gluten-sensitive enteropathy an environmentally induced autoimmune disease with genetic predisposition for certain HLA types Gln  Glu

29. Figure 11-29 Antibodies against streptococcal cell-wall antigens cross-react with antigens on heart tissue (P13.31) Molecular mimicry

30. Treatment of autoimmune diseases Immunosuppressant (eg cyclosporins) Anti-inflammatory drugs (eg steroids) Replacement therapy (eg insulin, thyroid hormone) eg. including transplantation of pancreatic insulin- producing cells for insulin-dependent diabetes Feeding or oral tolerance (induce tolerance to antigen) Feed insulin for diabetes Collagen for rheumatoid arthritis Cause local intestinal immune response, down regulation of antigen receptors deletion of immune cells

31. Figure 11-37 (P11.37)